Salt of phenethylbarbituric acid



Um'rdfiw Patent .1 Claim. (Cl. 260-2564) This application is a divisional application of application Ser. No. 102,139, filed Apr. 11, 1961, now US. Patent 3,210,247.

The present invention relates toa new and valuable salt of phenylethylbarbituric acid and more particularly to the crystalline addition compound of phenylethylbarbituric acid and cyclohexylisopropyl methylamine, to a process of preparing said compound, and to the use of said compound in the treatment of epilepsy.

Phenylethylbarbituric acid has proved to be a highly effective drug in the treatment of epilepsy. However, in addition to its anti-epileptic effect, it possesses an undesired sedative activity. Frequently, it causes incapacitating drowsiness so that patients who have to take such drugs during the daytime, make a :somnolent and indifferent impression. This undesirable sedative effect of phenylethylbarbituric acid is the'rnain factor limiting its usefulness as an anti-epileptic drug.

Attempts have been made to compensate for the sedative etfect of phenylethylbarbituric acid by simultaneously administering arousal amines, such as amphetamine or its N-methyl derivative. However, all these attempts were rather unsuccessful, because such arousal amines have too strong a stimulating effect and, thus tend to eliminate the' anti-epileptic effect of phenylethylbarbituric acid.

It is one object of the present invention to provide a phenylethylbarbituric acid compound which is substantially free of sedative activity while it still possesses its desired anti-epileptic activity.

Another objectof the present invention is to provide a process of preparing suoh'an anti-epileptic phenylethylbarbituric acid compound which'is substantially free of sedative activity.

Still another objject of the present invention is to provide a process of treating epilepsy by administration of the new phenylethylbarbituric acid compound.

A further object of the present invention is to provide an anti-epileptic composition which is free of the undesirable sedative activity of phenylethylbarbituric acid.

Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

In principle the new phenylethylbarbituric acid compound is obtained by combining phenylethylbarbituric acid with l-cyclohexyl-Z-methylamino propane. The resulting salt-like addition compound is a well-defined crystalline compound which has theanti-epileptic of phenylethylbarbituric acid, but no sedative activity.

Animal tests have shown that the new salt-like compound of phenylethylbarbituric acid and l-cyclohexyl-Z- methylamino propane has a substantially higher antiepileptic effect than phenylethylbarbituric acid and 1- cyclohexyl-2-methylamino isopropane when administered simultaneously in corresponding doses.

In contrast thereto the salt-like compounds of phenylethylbarbituric acid and amphetamine, or, respectively, its N-methyl derivative, although they have no appreciable sedative eifect, have the disadvantage that the antiepileptic activity of phenylethylbarbituric acid is also eliminated as can be shown in animal experiments. Said compounds have a high-analeptic effect as can be seen in laboratory animals by their purposeless and random movements. Thus, the stimulating activity of said compounds rneders them unsuitable for the treatment of epilepsy.

The new compound is prepared, for instance, by reacting phenylethylbarbituric acid with the free l-cyclohexyl- Z-methylamino propane base in the presence or absence of a suitable solvent.

Another method of producing said new compound consists in reacting the alkali metal salt and especially the sodium salt of phenylethylbarbituric acid with a suitable acid addition salt of 1-cyclohexyl-2-methylamino propane, for instance, with its hydrochloride in a suitable solvent.

The new compound has a characteristic melting point and can be recrystallized from suitable organic solvents or from water without decomposition and cleavage to its components. It possesses a considerably increased solubility in water and in this respect differs advantageously from phenylethylbarbituric acid itself.

The following examples serve to illustrate the present invention without, however, limiting the same thereto.

EXAMPLE 1 There are dissolved 29 g. of phenylethylbarbituric acid in cc. of acetic acid ethyl ester while heating and 20 g. of 1-cyclohexyl-Z-methylamino propane in the form of the base are added thereto While stirring. The resulting solution is allowed to cool. Thereby, the salt of l-cyclohexyl-2-methylamino propane and phenylethylbarbituric acid is obtained in the form of fine needles. The yield is almost quantitative. The melting point of the new compound is 130133 C.

EXAMPLE 2 There are taken 25.4 g. of sodium salt of phenylethylbarbituric acid and 19.1 g. of l-cyclohexyl-2-methylamino propane hydrochloride and they are boiled under reflux in a mixture of cc. of acetic acid ethyl ester and 125 cc. of ethanol. After boiling for half an hour, the solution is filtered, while still hot, to separate the precipitated sodium chloride. The filtrate is concentrated by evaporation to about half its volume. After cooling 42.5 g. of the salt of 1-cyclohexyl-2-methylamino propane and of phenylethylbarbituric acid are obtained in crystalline form. Its melting point is -133 C.

The new compound was compared pharmacologically with the salt-like addition compound of phenylethylbarbituric acid and amphetamine, or respectively, the N- methyl derivative of amphetamine.

Determination of the toxic doses in mice shows that the new compound has a toxicity which is about 50% lower than that of the other compounds.

The following Table I illustrates the results obtained in determining the dose in mg. per kg. administered orally which causes death in 50% of the mice (LD TABLE 1 Compound: LD in mg./ k. g

Phenylethylbarbituric acid and l-cyclohexyl-2- methylamino propane 250.0 Phenylethylbarbituric acid and amphetamine 171.0 Phenylethylbarbituric acid and N-methyl amphetamine 172.0

Tests carried out to determine the antagonistic activity of the above mentioned three compounds against convulsions caused by the administration of pentylene tetrazol prove that all three compounds are effective with about the same 50% protective dose.

Lethal doses of nicotine, however, are more readily 3 antagonistically effected by administration of the new pectins; as binders, gelatin, gum arabic, methyl cellulose, compound, than by that of the two other compounds, as yeast extract, agar, tragacanth; and as lubricating agents, will become evident from Table II, wherein the 50% promagnesium stearate, stearic acid, and others. tective doses in mg./kg. on oral administration are given. In human therapy a single dose between 50 mg. and

TABLE II 5 250 mg. may be given. The preferred single dose is be tween 100 mg. and 150 mg., administered three times Compound g i g Nicolinez daily. The total daily dose may be between 50 mg. and

9 ISZO Pgwvlethylbarbimric acid and l'cycmhexyl' The new compound may also be used in the form of -methylam1no propane 20.5 13.0 Y Phenylethylbarbiturie acid and amphet- 10 suppositones and the like preparat1ons.

' Of COUT, many changes and VSIlatlOIlS ll] 1'16 IIICthOd amphetamine 30.0 of producing the new compound and of 1solat1ng and 1 50% protective dose against intravenous administration of 14.0 mg./ punfylrig. the the preparailol} of phinimacquncal kg. in mice. compositions containing the same, in its administration to kgflgiBCilVe dose against intravenous admlnistration of 1.0 mg./ 15 l iq patients F the ik y be d? a th skilled in the art in accordance with the principles set Further tests were carried out with the three compounds forth herein and in the claim annexed hereto. whereby mice were subjected to the action of a strong For instance, tablets may be prepared as follows: light ray focused on the tip of their trails. At the same The salt of the phenylethylbarbituric acid and l-cyclotime the motility of the animals was determined. The re- 0 hexyl-2-methylamino propane is mixed with dried corn sults of these tests are given in the following Table III starch, talc and a paste containing potato starch in 6% which indicates the increase in motility in percent over aqueous solution, then granulated and dried. Granulated that of control animals, not treated with the drugs. corn starch and talc are added to the granules which are TABLE III.DosE IN MGJKG. 0N ORAL ADMINISTRATION Compound 1.0 2.0 5.0 10.0 20.0 40.0 80.0

Phenylethylbarbiturie acid and l-cyclohexyI-Z-methylanrino propane 7.0 +3. 5 +65. 0 +121. 0 Phenylethylbarbiturlc acid and amphetamine -20.0 10.0 +1300 +1200 +l58.0 +128.0 Phenylethylbarhiturie N-methyl amphetamine +100 +220 +12l.0 +1700 +l57.0 +1080 It is evident that no excitation of the animal is caused then mixed thoroughly and pressed to tablets containing when administering the new compound according to the per unit dose 100.0 mg. of the salt, 80.9 mg. of corn present invention in therapeutic doses. Only when adstarch, 14.0 mg. of talc and 5.1 mg. of potato starch. ministering high doses, the animals exhibit increased mo- There could be noticed that the new compound postility. In contrast thereto, the other two compounds show sesses an activity of a different kind than that of the equiaconsiderable increase in motility at very low doses which molecular mixture of corresponding quantities of the are considerably below the therapeutically effective doses. sodium salt of phenylethylbarbituric acid and l-cyclo- Said compounds, therefore, cannot be used in the treathexyl-2-methylamino propane hydrochloride. Equal doses ment of epilepsy because the resulting stimulation and of the new compound and the above said mixture have excitation would render them useless. been tested in the electroshock tests in rats comparing their These data prove that the new compound has neither protective action against electrically caused convulsions the hypnotic effect of phenylethylbarbituric acid nor the and the obtained curves showing the degree of action in stimulating effect of 1-cycl0hexyl-2-methylamino propane. dependence of the administered doses according to Litch- The compound according to the present invention, thus, is field and Wilcoxon have been mathematically evaluated. an ideal anti-epileptic agent because it is free of the dis- Hereby it resulted a dissimilar rising angle of the curves tnrbing hypnotic effects of phenylethylbarbituric acid and of action in dependence of the administered doses which the stimulating effects of 1-cyclohexyl-2-methylamino propoint to the fact that in the new compound the peroral pane. resorption passes more favorable than in the mixture.

Further experiments have shown that the new com- The new compound reacts more favorable than the pound has an increased spasm-inhibiting effect, which is sodium salt of phenylethylbarbituric acid with regard to superior to that achieved when administering phenylthe solubility and the stability of aqueous solutions. One

ethylbarbituric acid alone. g. of the new compound dissolves at 20 C. in 100 ml. of The new compound is preferably administered orally water while phenylethylbarbituric acid in the same volume in the form of tablets, pills, powders, capsules, solutions, of water is only soluble up to 0.097 g. The 0.5% soluemulsions, suspensions, dispersions, and in any other suitation in water shows a pH of only 8.0 to 8.5 in comparison bl f r with a pH of 9.0 to 9.5 of the sodium salt of phenylethyl- In the case of powders, fine, uniform dispersions of the barbitnric acid. The stability of aqueous solutions against new compound within the diluting agent is of importance. acidifying and alkalizing agents, as they are present in Such a fine dispersion can be achieved, for instance, by the gastro-intestinal tract, is clearly better than in the mixing and milling the new compounds with a solid, pulsodium salt of phenylethylbarbituric acid.

verulent extending agent to the desired fineness, or by I claim:

impregnating the already milled, finely powdered, solid 1. The addition compound of S-ethyl-S-phenylbarbitucarrier with a solution of the active compound in water, ric acid and 1-cyclohexylisopropyl-Z-methylamine.

or a water miscible solvent and then removing the water or solvent. References Cited t As zolidtcglrrierls, which tarelsuitable for the manufac- UNITED STATES PATENTS ure 0 sin a e p armaceu ica prepara ions, various inert pulverulent distributing agents as they are conventionigz gg er-e-tz ally used in pharmaceutical compounding may be em 3,210,247 10/1965 Suranyi 167 65 ployed.

When preparing tablets, pills, powders, and the like, the commonly used diluting agents, binders, lubricants, and NICHOLAS RIZZO Pnmary Exammer' the like are added, such as sugar, lactose, talcum, starch, R. J. GALLAGHER, Assistant Examiner. 

1. THE ADDITION COMPOUND OF 5-ETHYL-5-PHENYLBARBITURIC ACID AND 1-CYCLOHEXYLISOPROPYL-2-METHYLAMINE. 